Colorectal cancer (CRC) is the second leading cause of cancer-related death, and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. Additionally, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We performed multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes prostaglandin E receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biological candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in prostaglandin-endoperoxide synthase 2 (PTGS2), prostaglandin E receptor 2 (PTGER2), or prostaglandin E receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure.
Colorectal adenoma; genetic association; prostaglandin signaling; prostaglandin metabolism; NSAIDs
Supravalvular aortic stenosis (SVAS) is caused by mutations in the elastin (ELN) gene and is characterized by abnormal proliferation of vascular smooth muscle cells (SMCs) that can lead to narrowing or blockage of the ascending aorta and other arterial vessels. Availability of patient-specific SMCs may facilitate studying disease mechanisms and developing novel therapeutic interventions.
Methods and Results
Here, we report the development of a human induced pluripotent stem cell (iPSC) line from a patient with SVAS caused by the premature termination in exon 10 of the ELN gene due to an exon 9 4-nucleotide insertion. We showed that SVAS iPSC-derived SMCs (iPSC-SMCs) had significantly fewer organized networks of smooth muscle alpha actin (SM α-actin) filament bundles, a hallmark of mature contractile SMCs, compared to control iPSC-SMCs. Addition of elastin recombinant protein or enhancement of small GTPase RhoA signaling was able to rescue the formation of SM α-actin filament bundles in SVAS iPSC-SMCs. Cell counts and BrdU analysis revealed a significantly higher proliferation rate in SVAS iPSC-SMCs than control iPSC-SMCs. Furthermore, SVAS iPSC-SMCs migrated at a markedly higher rate to the chemotactic agent platelet-derived growth factor (PDGF) in comparison with the control iPSC-SMCs. We also provided evidence that elevated activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is required for hyper-proliferation of SVAS iPSC-SMCs. The phenotype was confirmed in iPSC-SMCs generated from a patient with deletion of elastin due to Williams-Beuren syndrome (WBS).
Thus, SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.
elastin; induced pluripotent stem cells; smooth muscle alpha actin filament bundle; smooth muscle cells; supravalvular aortic stenosis
Background Whether soy food consumption may protect against coronary heart disease (CHD) remains controversial. No previous study has used biomarkers of soy intake in assessing the relationship between soy consumption and CHD. Biomarkers that reflect both intake and metabolism may be more informative than self-reports of dietary intake.
Methods We examined associations of urinary isoflavonoids, a biomarker of soy or soy isoflavone intake, with risk of CHD in a case–control study nested within two prospective cohort studies of Chinese adults in Shanghai. Cases were defined as subjects with no history of CHD at baseline who developed incident CHD during follow-up. Control subjects were randomly selected from those who remained free of CHD and matched to cases by sex, age, date and time of sample collection and antibiotic use. Baseline urinary isoflavonoids (daidzein, genistein, glycitein, equol, O-desmethylangolensin, dihydrodaidzein and dihydrogenistein) were compared between cases (n = 377) and control subjects (n = 753). Conditional logistic regression was used to evaluate the associations.
Results Total urinary isoflavonoids were not associated with CHD in either women or men. However, urinary equol excretion showed a significant inverse association with CHD in women. The adjusted odds ratios (95% confidence intervals) for CHD across increasing quartiles of equol levels in women were 1 (reference), 0.61 (0.32, 1.15), 0.51 (0.26, 0.98) and 0.46 (0.24, 0.89) (P = 0.02 for trend).
Conclusions Our study suggests for the first time that equol, a bioactive metabolite of soy isoflavone daidzein, may be inversely associated with risk of CHD in women.
coronary disease; isoflavones; soy foods
To provide a basis for improved prevention and treatment of hepatitis B virus (HBV) re-infection after liver transplantation, variations in the S and P genes of HBV under immunosuppression in vitro and their association with patient prognosis were investigated. For the in vitro study, HepG2.2.15 hepatocellular carcinoma cells stably producing HBV particles were treated with the immunosuppressants methylprednisolone (MP) and tacrolimus (FK506) at doses found to be non-toxic by the methylthiazolyl tetrazolium (MTT) cell viability assay. MP dose-dependently inhibited HBV DNA expression in HepG2.2.15 cells, while FK506 did not, as determined by quantitative real-time PCR (qRT-PCR). By gene sequencing, both MP and FK506 were found to cause variations in HBV S, P, and S/P overlapping regions. MP- but not FK506-induced mutations were common in the glucocorticoid response element of the P region, while both immunosuppressants caused mutations outside the nucleoside analogue resistance sites. For the in
vivo study, 14 patients with HBV-related end-stage liver disease re-infected after liver transplantation, and 20 cases without HBV re-infection as controls, were studied. Seventy-five percent of re-infected recipients showed multi-loci amino acid mutations at different sites besides lamivudine (LAM)-resistant loci in the P region, including in the glucocorticoid response element. Fifty percent of re-infected recipients had mutations in the “a” determinant region and flanking sequences. Re-infection was associated with negative serum hepatitis B immunoglobulin (HBIG), as measured by a microparticle capture enzyme immunoassay. Nucleotide mutations in the S region caused missense or synonymous mutations, which caused synonymous mutations in the overlapping P region. These results showed that effects of immunosuppressants on HBV genes in vitro were different from those in clinical recipients. Positive HBV DNA and gene mutations pre-transplantation were factors affecting re-infection post-transplantation. Multiple mutations found in the P and S genes suggest that the formation of quasispecies contributes to HBV re-infection after liver transplantation.
Telomeres are specialized chromatin structures essential for maintenance of chromosomal integrity and stability. Abnormal alteration of telomere length has been linked to several cancers; however, epidemiologic evidence regarding the association of telomere length with colorectal cancer risk has been conflicting.
We conducted a nested case-control study to evaluate the association between telomere length and colorectal cancer risk using peripheral blood samples collected prior to cancer diagnosis. The study included 441 women with incident colorectal cancer and 549 matched controls. Monochrome multiplex quantitative PCR was applied to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios (OR) with 95% confidence intervals (CI) as the measure of association between telomere length and subsequent colorectal cancer risk.
A U-shaped association was observed between telomere length and colorectal cancer risk (test for nonlinearity P = 0.0112). Women with telomere length in the third quintile (40th to 60th percentiles) had the lowest risk of colorectal cancer, and the risks were elevated with a shorter or longer telomere length. This U-shaped association did not statistically differ for colon cancer and rectum cancer.
Conclusions and Impact
Our prospective study revealed a U-shaped association between telomere length in peripheral blood cells and colorectal cancer risk. Our findings provide strong evidence that both very short and very long telomeres are associated with increased risk of colorectal cancer.
Abnormal sleep duration, either long or short, is associated with disease risk and mortality. Little information is available on sleep duration and its correlates among Chinese women.
Using information collected from 68,832 women who participated in the Shanghai Women’s Health Study (SWHS), we evaluated sleep duration and its correlations with sociodemographic and lifestyle factors, health status, and anthropometric measurements and their indexes using polynomial logistic regression.
The mean age of the study population was 59.6 years (SD=9.0; range: 44.6–79.9 years) at time of sleep duration assessment. Approximately 80% of women reported sleeping 6–8 hours per day, 11.5% slept five hours or less, and 8.7% slept nine hours or more. As expected, age was the strongest predictor for sleep duration and was negatively correlated with sleep duration. In general, sleep duration was positively associated with energy intake, intakes of total meat and fruits, body mass index (BMI), waist-hip ratio (WHR), and waist circumference (WC) after adjustment for age and other factors. Both short and long sleep duration were negatively associated with education level, family income, and leisure-time physical activity and positively associated with number of live births, history of night shift work, and certain chronic diseases, compared to sleep duration around seven hours/day (6.5–7.4 hours/day). Short sleep duration was related to tea consumption and passive smoking. Long sleep duration was related to menopausal status and marital status.
In this large, population-based study, we found that sleep duration among middle-aged and elderly Chinese women was associated with several sociodemographic and lifestyle factors and with disease status. The main limitation of the study is the cross-sectional design that does not allow us to draw any causal inference. However, this study provides information for future investigation into the nature of these associations so that recommendations can be developed to reduce sleep problems in middle-aged and elderly Chinese women. It also provides important information on potential confounders for investigation of sleep duration on health outcomes in this population.
Sleep duration; socio-economic factor; lifestyle; health status; BMI; correlation; Chinese
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
Most epidemiological studies evaluating the association of fruit and vegetable intakes on lung cancer risk were conducted in North American and European countries. We investigated the association of intakes of fruits, vegetables, dietary vitamins A and C, and folate with lung cancer risk among 61,491 Chinese adult men who were recruited to the Shanghai Men's Health Study, a population-based, prospective cohort study. Baseline dietary intake was assessed through a validated food frequency questionnaire during in-home visits. Multivariate Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of lung cancer risk associated with dietary intakes. During a median follow-up of 5.5 years, 359 incident lung cancer cases accrued after the first year of follow-up and 68.8% of them were current smokers. Intakes of green leafy vegetables, β-carotene-rich vegetables, watermelon, vitamin A, and carotenoids were inversely associated with lung cancer risk; the corresponding HR (95% CI) comparing the highest with the lowest quartiles were 0.72 (0.53–0.98), 0.69 (0.51–0.94), 0.65 (0.47–0.90), 0.63 (0.44–0.88), and 0.64 (0.46–0.88). Intake of all fruits and vegetables combined was marginally associated with lower risk. Our study suggests that the consumption of carotenoid-rich vegetables is inversely associated with lung cancer risk.
fruits; vegetables; carotenoids; dietary intake; lung cancer; epidemiological
Previous studies suggest that melatonin may act on cancer growth through a variety of mechanisms, most notably by direct anti-proliferative effects on breast cancer cells and via interactions with the estrogen pathway. Three genes are largely responsible for mediating the downstream effects of melatonin: melatonin receptors 1a and 1b (MTNR1a and MTNR1b), and Arylalkylamine N-acetyltransferase (AANAT). It is hypothesized that genetic variation in these genes may lead to altered protein production or function. To address this question, we conducted a comprehensive evaluation of the association between common single nucleotide polymorphisms (SNPs) in the MTNR1a, MTNR1b, and AANAT genes and breast cancer risk among 2,073 cases and 2,083 controls, using a two-staged analysis of genome-wide association (GWAS) data among women of the Shanghai Breast Cancer Study. Results demonstrate two SNPS were consistently associated with breast cancer risk across both study stages. Compared with MTNR1b rs10765576 major allele carriers (GG or GA), a decreased risk of breast cancer was associated with the AA genotype (OR=0.78, 95% CI=0.62–0.97, p=0.0281). Although no overall association was seen in the combined analysis, the effect of MTNR1a rs7665392 was found to vary by menopausal status (p-value for interaction=0.001). Premenopausal women with the GG genotype were at increased risk for breast cancer as compared to major allele carriers (TT or TG) (OR=1.57, 95% CI=1.07–2.31, p=0.020), while post-menopausal women were at decreased risk (OR=0.58, 95% 0.36–0.95, p=0.030). No significant breast cancer associations were found for variants in AANAT. These results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. Given that multiple variants in high linkage disequibrium with MTNR1b rs76653292 have been associated with altered function or expression of insulin and glucose family members, further research may focus on clarifying this relationship.
Melatonin; gene; polymorphism; breast cancer; risk
The authors evaluated the prognostic effects of obesity and weight change after breast cancer diagnosis. A total of 5042 breast cancer patients aged 20–75 were identified through the population-based Shanghai Cancer Registry approximately 6 months after cancer diagnosis and recruited into the study between 2002 and 2006. Participants were followed by in-person interviews supplemented by record linkage with the Shanghai Vital Statistics Registry database. Anthropometric measurements were taken and information on sociodemographic, clinical, and lifestyle factors was collected through in-person interviews. During the median follow-up of 46 months, 442 deaths and 534 relapses/breast cancer-specific deaths were documented. Women with body mass index (BMI) ≥30 at diagnosis had higher mortality than women with 18.5≤BMI<25; the multivariate adjusted hazard ratios (HRs) were 1.55 (95% confidence interval (95% CI): 1.10–2.17) for total mortality and 1.44 (95% CI: 1.02–2.03) for relapse/disease-specific mortality. Similar results were found for pre- and post-diagnostic obesity. Women who gained ≥5kg or lost >1kg had higher mortality than those who maintained their weight. No association was observed between waist-to-hip ratio and mortality. Our study suggests that obesity and weight change after diagnosis are inversely associated with breast cancer prognosis. Weight control is important among women with breast cancer.
Body mass index; central obesity; weight change; breast cancer; survival
Previous studies of the association of meat intake and meat-derived mutagen exposure with breast cancer risk have produced inconsistent results. We evaluated this association in a population-based case-control study of incident breast cancer conducted in Nashville, United States, including 2,386 breast cancer cases and 1,703 healthy women controls. Telephone interviews were conducted to obtain information related to meat intake including amount, cooking methods, and doneness levels, as well as other known or hypothesized risk factors for breast cancer. Unconditional logistic regression was used to derive odds ratios (ORs) after adjusting for potential confounders. High intake of red meat was associated with a significantly elevated risk of breast cancer (P-trend <0.001). The association was particularly strong for high intake of well-done red meat (P-trend <0.001), with an adjusted OR of 1.5 (95% CI = 1.3–1.9) for the highest versus the lowest quartile. Associations between red meat and breast cancer risk were slightly stronger for postmenopausal women than for premenopausal women. Meat-derived mutagens such as 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, were significantly associated with increased breast cancer risk among postmenopausal women only (P-trend = 0.002 and 0.003, respectively). The results from this study provide strong support for the hypotheses that high red meat intake and meat-derived mutagen exposure may be associated with an increase in breast cancer risk.
Dietary factors; nutrition epidemiology; meat-derived mutagens; heterocyclic amines breast cancer
Gestational zinc deficiency has been confirmed to impair the infant immune function. However, knowledge about effects of maternal mild zinc deficiency during pregnancy on hepatitis B vaccine responsiveness in offspring is limited. In this report, we aimed to examine how maternal zinc deficiency during pregnancy influences humoral and cellular immune responses to hepatitis B vaccination in offspring of BALB/c mice.
From day 1 of pregnancy upon delivery, maternal mice were given a standard diet (30 mg/kg/day zinc), zinc deficient diet (8 mg/kg/day zinc), or combination of zinc deficient diet (8 mg/kg/day zinc in the first 2 weeks of gestation) and zinc supplement diet (150 mg/kg/day zinc for the last week of pregnancy), respectively. Newborn pups of these maternal mice were immunized with hepatitis B vaccine at postnatal weeks 0, 2 and 4. Then, splenocytes and blood samples from the offspring mice were harvested for detection of serum zinc concentrations, humoral and cell-mediated immune responses, expression of cytokines using ELISA, CCK-8 and flow cytometric analysis. Results from the present study demonstrated that gestational zinc deficiency inhibited antibody responses, and decreased the proliferative capacity of T cells in offsprings immunized with hepatitis B vaccine. Additionally, HBsAg-specific cytokines analysis revealed that gestational zinc deficiency could inhibit secretion of IFN-γ from splenocytes, and decrease IFN-γ expression of CD4+ and CD8+ T cells.
Gestational zinc deficiency can weaken the humoral and cell-mediated immune responses to hepatitis B vaccine via decreasing B cell counts and hepatitis B virus-specific immunoglobulin G production, as well as reducing T cell proliferation, CD4+/CD8+ T cell ratio, and Th1-type immune responses.
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity, but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease, but remains expensive, inconvenient and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of non-iminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermo-stabilize GAA, and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models.
We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.
Patients and Methods
Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.
Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84–2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19–1.76]), obesity (body mass index >30 kg/m2) (OR: 1.26 [1.09–1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13–2.18], case-control OR: 1.80 [1.40–2.32]), family history of pancreatic cancer (OR: 1.60 [1.20–2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10–1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97–2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19–1.40]), rs401681(5p15.33) (OR: 1.18 [1.10–1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18–1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.
Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.
Few data are available regarding depression among Asian breast cancer survivors.
We estimated the prevalence of depression and its correlates among 1400 participants of a population-based cohort study of women with stage 0–IV breast cancer in Shanghai, China. Through in-person interviews conducted at 6 months and 18 months post-diagnosis and review of medical charts, information on sociodemographic and clinical factors and quality of life (QOL) were collected. Depression was measured by the 20-item Center for Epidemiologic Studies Depression Scale 18 months after diagnosis.
Approximately 26% of participants had mild to severe depression and 13% fulfilled the criteria of clinical depression at 18 months post-diagnosis. Women with lower income were more likely to have depression than those with higher income (prevalence: 16.6% vs. 6.9% for mild depression and 17.1% vs. 5.5% for clinical depression, respectively). Depression was more common among women who were widowed (18.9%) or divorced/separated/single (16.4%) than those who were married (11.8%). Women with comorbidity were more likely to have clinical depression (17.3% vs 11.2%). Multivariate analysis showed that low income, marital status, comorbidity, and low QOL scores were independent predictors for depression. We did not find that prevalence of depression differed by menopausal status, estrogen or progesterone receptor status, disease stage, or cancer-related treatments.
Depression is common among Asian women with breast cancer. Routine screening and prevention of depression are warranted among women with breast cancer.
depression; breast cancer; prevalence; risk factor
Emerging evidence supports an inhibitory role for vitamin D in colorectal carcinogenesis, but the mechanism remains unclear. The APC/β-catenin pathway plays a critical role in colorectal carcinogenesis. The purpose is this study is to explore the interactions of vitamin D and APC/β-catenin pathways in intestinal tumor development. APCmin/+ mice with genetic inactivation of the vitamin D receptor (VDR) were generated through breeding. Intestinal tumorigenesis was compared between APCmin/+ and APCmin/+VDR−/− mice at different ages. No differences were seen in the number of small intestinal and colonic tumors between APCmin/+ and APCmin/+VDR−/− mice at 3, 4 and 6–7 months of age. The size of the tumors, however, was significantly increased in APCmin/+VDR−/− mice in all age groups. Immunostaining showed a significant increases in β-catenin, cyclin D1, phosphorylated Stat-3 and MSH-2 levels and decreases in Stat-1 in APCmin/+VDR−/− tumors compared to APCmin/+ tumors. These observations suggest that VDR signaling inhibits tumor growth rather than tumor initiation in the intestine. Thus, the increased tumor burden in APCmin/+VDR−/− mice is likely due to the loss of the growth-inhibiting effect of VDR. This study provides strong evidence for the in vivo relevance of the interaction demonstrated in vitro between the vitamin D and β-catenin signaling pathways in intestinal tumorigenesis.
vitamin D receptor; beta-catenin; intestinal tumor; colon cancer; Apc(min/+)
Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we undertook a genome-wide association study involving 1,265 endometrial cancer cases from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. Genotype frequencies in cases and controls were compared for 519,655 SNPs. Forty-seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B on chromosome 17q (SNP rs4430796: P=7.1×10−10), that is also associated with risk of prostate cancer and is inversely associated with type 2 diabetes.
In a population-based cohort study of 5014 women with stage 0–III breast cancer, we evaluated weight change patterns from diagnosis to 6, 18, and 36 months post-diagnosis. Patients were recruited to the study approximately 6 months after cancer diagnosis between 2002 and 2006 and followed through 36 months post-diagnosis. The medians of weight change from diagnosis to 6, 18, and 36 months post-diagnosis were 1.0 kg, 2.0 kg, and 1.0 kg, respectively. Approximately 26% of survivors gained ≥5% of their at-diagnosis body weight during the first 6 months after diagnosis, while 37% and 33% of women gained the same percentage of weight at 18 and 36 months post-diagnosis. More weight gain was observed among women who had a more advanced disease stage, were younger, had lower body mass index at diagnosis, were premenopausal, or received chemotherapy or radiotherapy during the first 6 months after cancer diagnosis. Multivariate analyses indicated that age at diagnosis, body size, comorbidity, and disease stage independently predicted weight gain from diagnosis to 36 months post-diagnosis. In summary, weight gain is common over the first 3 years after breast cancer diagnosis among Chinese women. More research is needed to investigate measures to prevent weight gain in breast cancer survivors.
weight change pattern; breast cancer; survivor; Chinese population
Previous studies in humans and animals have suggested a possible association between lead (Pb) exposure and the etiology of Alzheimer’s disease (AD). Animals acutely exposed to Pb display an over-expressed amyloid precursor protein (APP) and the ensuing accumulation of beta-amyloid (Aβ) in brain extracellular spaces. This study was designed to examine whether in vivo Pb exposure increased brain concentrations of Aβ, resulting in amyloid plaque deposition in brain tissues. Human Tg-SWDI APP transgenic mice, which genetically over-express amyloid plaques at age of 2-3 months, received oral gavages of 50 mg/kg Pb acetate once daily for 6 wk; a control group of the same mouse strain received the same molar concentration of Na acetate. ELISA results revealed a significant increase of Aβ in the CSF, brain cortex and hippocampus. Immunohistochemistry displayed a detectable increase of amyloid plaques in brains of Pb-exposed animals. Neurobehavioral test using Morris water maze showed an impaired spatial learning ability in Pb-treated mice, but not in C57BL/6 wild type mice with the same age. In vitro studies further uncovered that Pb facilitated Aβ fibril formation. Moreover, the synchrotron X-ray fluorescent studies demonstrated a high level of Pb present in amyloid plaques in mice exposed to Pb in vivo. Taken together, these data indicate that Pb exposure with ensuing elevated Aβ level in mouse brains appears to be associated with the amyloid plaques formation. Pb apparently facilitates Aβ fibril formation and participates in deposition of amyloid plaques.
Lead or Pb; beta-amyloid or Aβ; amyloid plaques; Tg-SWDI mouse; fibril formation; X-ray fluorescence or XRF; hippocampus
In recent pooled analyses among whites and Asians, mortality was shown to rise markedly with increasing body mass index (BMI; weight (kg)/height (m)2), but much less is known about this association among blacks. This study prospectively examined all-cause mortality in relation to BMI among 22,014 black males, 9,343 white males, 30,810 black females, and 14,447 white females, aged 40–79 years, from the Southern Community Cohort Study, an epidemiologic cohort of largely low-income participants in 12 southeastern US states. Participants enrolled in the cohort from 2002 to 2009 and were followed up to 8.9 years. Hazard ratios and 95% confidence intervals for mortality were obtained from sex- and race-stratified Cox proportional hazards models in association with BMI at cohort entry, adjusting for age, education, income, cigarette smoking, and alcohol consumption. Elevated BMI was associated with increased mortality among whites (hazard ratios for BMI >40 vs. 20–24.9 = 1.37 (95% confidence interval (CI): 1.02, 1.84) and 1.47 (95% CI: 1.15, 1.89) for white males and white females, respectively) but not significantly among blacks (hazard ratios = 1.13 (95% CI: 0.89, 1.43) and 0.87 (95% CI: 0.72, 1.04) for black males and black females, respectively). In this large cohort, obesity in mid-to-late adulthood among blacks was not associated with the same excess mortality risk seen among whites.
African Americans; body mass index; mortality
The aim of present research is to analyze the detailed changes of dendritic cells (DCs) induced by pidotimod(PTD). These impacts on DCs of both bone marrow derived DCs and established DC2.4 cell line were assessed with use of conventional scanning electron microscopy (SEM), flow cytometry (FCM), transmission electron microscopy (TEM), cytochemistry assay FITC-dextran, bio-assay and enzyme linked immunosorbent assay (ELISA). We demonstrated the ability of PTD to induce DC phynotypic and functional maturation as evidenced by higher expression of key surface molecules such as MHC II, CD80 and CD86. The functional tests proved the downregulation of ACP inside the DCs, occurred when phagocytosis of DCs decreased, with simultaneously antigen presentation increased toward maturation. Finally, PTD also stimulated production of more cytokine IL-12 and less TNF-α. Therefore it is concluded that PTD can markedly exert positive induction to murine DCs.
pidotimod; dendritic cells; phagocytosis; maturation; immunomodulation
The effects of diet on breast cancer are controversial and whether the effects vary with hormone receptor status has not been well investigated. This study evaluated the associations of dietary factors with risk for breast cancer overall and by hormone receptor status of tumors among Chinese women.
The Shanghai Breast Cancer Study, a large, population-based, case-control study, enrolled 3,443 cases and 3,474 controls in 1996–1998 (phase I) and 2002–2004 (phase II); 2,676 cases had ER and PR data. Dietary intake was assessed using a validated, quantitative, food frequency questionnaire (FFQ). Odds ratios (ORs) and 95% confidence intervals (95% CI) were derived from multivariate, polychotomous, unconditional logistic regression models.
Total vegetable intake was inversely related to breast cancer risk, with an adjusted OR for the highest quintile of 0.80 (95% CI = 0.67–0.95; P trend=0.02). Reduced risk was also related to high intake of allium vegetables (P trend = 0.01) and fresh legumes (P trend = 0.0008). High intake of citrus fruits and rosaceae fruits were inversely associated with breast cancer risk (P trend = 0.003 and P trend = 0.004, respectively), although no consistent association was seen for total fruit intake. Elevated risk was observed for all types of meat and fish intake (all P trend <0.05), while intakes of eggs and milk were associated with a decreased risk of breast cancer (both P trend <0.05). There was little evidence that associations with dietary intakes varied across the four tumor subtypes or between ER+/PR+ and ER−/PR− tumors (P for heterogeneity >0.05).
Our results suggest that high intake of total vegetables, certain fruits, milk, and eggs may reduce the risk of breast cancer, while high consumption of animal-source foods may increase risk. The dietary associations did not appear to vary by ER/PR status.
A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.
Rats that consume high-energy (HE) diets (i.e., diets high in saturated fats and sugar) show impaired hippocampal-dependent learning and memory (e.g., ). To further investigate this effect, we trained rats given restricted access to low-fat lab chow on hippocampal-dependent serial feature-negative (FN) and hippocampal-independent simple discrimination problems. When training was completed, Group Chow received ad libitum lab chow. The remaining rats received ad libitum HE diet. Performance on both discrimination problems was tested following 7, 14, 21 and 28 days of HE diet exposure. FN, but not simple discrimination, was abolished initially for all rats, and then re-emerged for Group Chow. For rats fed HE diet, those that weighed the least and had lowest amount of body fat (HE-diet resistant (HE-DR) rats), performed like Group Chow on both discrimination problems. However, HE diet-induced obese (HE-DIO) rats (i.e., rats that weighed the most weight and had the most body fat) performed like Group Chow on the simple discrimination problem, but were impaired throughout testing on the FN problem. Subsequent assessment of blood-brain barrier (BBB) permeability revealed that concentrations of an exogenously administered dye were elevated in the hippocampus, but not in the striatum or prefrontal cortex for HE-DIO rats relative to the HE-DR and Chow groups. The results indicate that the adverse consequences of HE diet on hippocampal-dependent cognitive functioning are associated with detrimental effects on the BBB and that both of these outcomes vary with sensitivity to HE diet-induced increases in weight and adiposity.
hippocampus; high-fat diet; obesity; learning; adiposity; energy balance; cognition